Macrophage participation in the hepatic response to acute CNS injury.

Lead Research Organisation: University of Oxford
Department Name: Pharmacology

Abstract

We are committed to improving public engagement in science and we will ensure that work carried under under this proposal will be communicated to those outside the scientific community. We have established a web site to disseminate details of our research (www.pharm.ox.ac.uk). If the application is successful, the lay summary will be placed on the web sites, which will be updated as the milestones are reached. We have given, and will be giving, public lectures on the theme of this proposal, we are also involved in a local Schools science programme, and we will release items about our work to the Oxford University Press Office after they have been published in peer-reviewed journals.

Technical Summary

Local tissue inflammation is also accompanied by regulatory responses in organs away from the primary injury site, which is known as the systemic Acute Phase Response (APR). Injury to the brain or spinal cord also generates an APR. We have discovered, using GeneChip analysis, convention molecular biology, and immuno methods, that the APR after brain injury results in the activation of cells in the liver to produce molecules, known as chemokines, which increase the number of immune cells circulating in the blood. These increased numbers of immune cells migrate not only into the brain where they damage nerve cells, but also into the liver where they cause injury. There is now a need to understand the signalling events that regulate this system and to learn more about the cell populations that are responsible for steering the hepatic APR to CNS injury. Under this proposal, we will test our hypothesis that resident microglia in the brain and Kupffer cells in the liver are the primary mediators of the hepatic APR. We will employ three strategies to target macrophage function in the periphery and in the CNS: (1) we will use newly developed CD11b-HSVTK transgenic mice to achieve microglial paralysis, (2) we will employ peripheral injections of clodronate filled liposomes to selectively deplete Kupffer cells in the liver, and (3) we will suppress Kupffer cell function by the use of a replication deficient adenovirus expressing the IkBa super-repressor gene, which will block NFkB activity. In this way, we expect to discover that elimination or suppression of microglial function in the brain will prevent the initiation of an acute phase response to CNS injury and that the Kupffer cell inactivation will lead to a decrease in the production of hepatic chemokines and a decrease in the mobilisation and recruitment of neutrophils to the liver and to the brain. Furthermore, it is still unclear how macrophage populations contribute to the febrile response. We will use telemetry to discover how microglial paralysis or Kupffer cell depletion contributes to the febrile response initiated by CNS injury. Understanding the cellular and molecular pathways that control the liver-brain axis in the inflammatory response to brain injury will open up therapeutic avenues that can be exploited for clinical treatments to reduce damage to the brain and spinal cord, a significant cause of human morbidity.

Publications

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Van Kasteren SI (2009) Glyconanoparticles allow pre-symptomatic in vivo imaging of brain disease. in Proceedings of the National Academy of Sciences of the United States of America

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Campbell SJ (2008) Hepatic nuclear factor kappa B regulates neutrophil recruitment to the injured brain. in Journal of neuropathology and experimental neurology

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Serres S (2009) Systemic inflammatory response reactivates immune-mediated lesions in rat brain. in The Journal of neuroscience : the official journal of the Society for Neuroscience

 
Description Epilepsy 
Organisation Wellcome Trust
Department Wellcome Trust Cente for Neuroimaging
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of histology, molecular biology and imaging reagents
Collaborator Contribution Post-doctoral salary
Impact The manuscript has been submitted, but has not been accepted. However, the following abstract has been accepted for presentation at http://www.epilepsyrhodes2010.org/ and could be presented as a outcome of the collboration. We have also submitted two grants on the basis of this collaboration; one the EU entitled INDICATE, and an application for a John Fell award here in Oxford.
Start Year 2007
 
Title Multimeric iron oxide particles 
Description We have developed a new platform for imaging. See pubs. 
IP Reference WO2008035069 
Protection Patent granted
Year Protection Granted 2008
Licensed Commercial In Confidence
Impact Commercial in confidence
 
Title Tumour vasculature permeabilising agents 
Description The present invention provides a tumour vasculature permeabilising molecule for use in permeabilising vasculature of a tumour for treating, detecting or diagnosing said tumour wherein said tumour vasculature permeabilising molecule is formulated for systemic administration to said patient. A composition comprising a tumour vasculature permeabilising molecule and an appropriate anticancer agent or imaging agent, and a method of treatment or a method of detecting the presence or absence of a tumour are also provided. 
IP Reference WO2011070358 
Protection Patent granted
Year Protection Granted 2011
Licensed Commercial In Confidence
Impact Commercial in Confidence
 
Title Adjunct therapby for brain cancer 
Description Commercially sensitive information 
Type Therapeutic Intervention - Drug
Current Stage Of Development Initial development
Year Development Stage Completed 2009
Development Status Actively seeking support
Impact Commercially sensitive information 
 
Company Name Oxford Contrast 
Description The company is seeking to produce targeted contrast agent for use in MRI and PET; http://www.oxfordcontrast.com/ 
Year Established 2009 
Impact First round funding expected Jan 2010
 
Description School visits 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Primary Audience Schools
Results and Impact A description of the science we do including discussion aboout the ethics of animal experimentation.

None
Year(s) Of Engagement Activity 2006,2007,2008,2009